This invention relates to the use of triol triester derivatives as edible synthetic fat replacements in food and pharmaceuticals. These compounds have a four- to thirty- carbon backbone to which are attached three fatty C.sub.1 or C.sub.2 to C.sub.29 aliphatic, ether, or ester groups in ester linkage. Preferred compounds are partially digestible.
Reduction in caloric intake can be significantly enhanced by dietary fat reduction, since fats provide nine calories per gram compared to four calories per gram provided by protein or carbohydrates. Furthermore, dietary fats represent a large percentage (approximately 40) of the daily caloric intake (Merten, H. L., 18 J. Agr. Food Chem. 1002 (1970)). Not only are fats high in calories, but certain fats appear to pose a health risk when consumed in large quantities over time. In 1988, the Surgeon General issued a report, "Nutrition and Health, " which summarized available scientific evidence for the role of diet in health promotion and disease prevention, and comprehensively documented the basis for recommended dietary changes. A main conclusion of this report was that overconsumption of certain dietary components is now a major concern for Americans, who disproportionately consume foods high in fat, often at the expense of foods high in complex carbohydrates and fiber that may be more conducive to health (Altschul, A. M., "Low Calorie Foods " Scientific Status Summary, Institute of Food Technologists, April 1989). A number of other national advisory committees on nutrition have made recommendations differing in detail, but the common theme is a reduction in the total amount of fat in the diet (Gottenbos, J. J., chapter 8 in Beare-Rogers, J., ed., Dietary Fat Requirements in Health and Development, A.O.C.S. 1988, page 109). Hence, major research efforts have focused on ways to produce food substances that provide the same functional and organoleptic properties as fats, but not the calories.
A major strategy for developing low calorie replacement fats has been to structurally re-engineer natural triglycerides in such a way as to retain their conventional functional properties in foods, while removing their susceptibility toward hydrolysis or subsequent absorption during digestion. To this end, the fatty acids attached to glycerol have been replaced with alternate acids (U.S. Pat. No. 3,579,548 to Whyte and U.S. Pat. No. 4,582,715 to Volpenhein); groups have been inserted between the fatty acids and the glycerol backbone ("propoxylated glycerols", U.S. Pat. No. 4,861,613 to White and Pollard); the ester linkages have been replaced by ether linkages (Can. Pat. No. 1,106,681 to Trost); the ester linkages have been reversed (U.S. Pat. No. 4,508,746 to Hamm); and the glycerol moeity has been replaced with an alternate alcohol (e.g., ethylene glycol in U.S. Pat. No. 2,924,528 to Barskey et al., and U.S. Pat. No. 2,993,063 to Alsop and Carr).
A second major approach to the development of a low calorie fat replacement has been to explore or synthesize non-absorbable polymeric materials structurally unlike triglycerides, but having physical properties similar to edible fat. Mineral oil was disclosed as early as 1894 (U.S. Pat. No. 519,980 to Winter), and, more recently, polydextrose (U.S. Pat. No. 4,631,196 to Zeller), polyglucose and polymaltose (U.S. Pat. No. 3,876,794 to Rennhard), polysiloxane (Eur. Pat. Ap. No. 205,273 to Frye), jojoba wax (W. Ger. Pat. No. 3,529,564 to Anika), and polyethylene polymers (E. Ger. Pat. No. 207,070 to Mieth, et al.) have been suggested.
A third major strategy combines the first two. Rather than restructure triglyceride molecules or find substitutes structurally very dissimilar, this approach explores the use of various polyol esters, compounds which have numbers of fatty acid groups in excess of the three in conventional fat triglycerides, as nonabsorbable fat replacements. Fully esterified sugar alcohols were suggested as fat replacements during World War I (notably mannitol, Lapworth, A., and Pearson, L. K., and Halliburton, W. D., et al., 13 J. Biol. Chem. 296 and 301 (1919)); Minich suggested esterifying pentaerythritol, a tetrahydric neopentyl sugar alcohol which can be formed from pentaerythrose, in 1960; and the Southern and Western Regional Research Laboratories of the U.S.D.A. investigated the feasibility of using amylose esters as new-type fats during the 1960's (see Booth, A. N., and Gros, A. T., 40 J. Amer. Oil Chem. Soc. 551 (1963) and the references cited therein). The same U.S.D.A. group further determined the caloric availability and digestibility of a series of dimeric and polymeric glycerides including diglyceride esters of succinic, fumaric, and adipic acids, and polymeric fats from stearic, oleic and short-chain dibasic acids for possible use as low calorie fats. Polyglycerol esters were suggested in 1972 (U.S. Pat. No. 3,637,774 to Babayan and Lehman).
Also in 1972, a series of papers was published which described studies assessing a series of compounds having from one to eight hydroxyl groups esterified with fatty acids. In vitro, purified pancreatic lipase did not hydrolyze polyols having more than three hydroxyl groups esterified (Mattson, F. H., and Volpenhein, R. A., 13 J. Lipid Res. 325 (1972), summarized in Table 1, page 327). However, a crude preparation of bile and pancreatic fluid hydrolyzed, to some extent, all substrates having from one to five ester groups esterified. Substrates having 6 to 8 hydroxyl groups esterified were not cleaved (ibid.). The investigators attributed the hydrolysis of substrates having four or five esterified groups to a "nonspecific lipase " that could be deactivated by the addition of a proteolytic enzyme, alpha-chymotrypsin (ibid, column 2, paragraph 2).
The "nonspecific lipase " also appeared to hydrolyze methyl oleate, ethylene glycol dioleate and glycerol trioleate in an enzyme preparation containing pancreatic lipase inhibited by taurocholate (see ibid., Table 1, and page 328, column 1, last paragraph, ending the article at column 2). A subsequent paper confirmed the stepwise hydrolysis of erythritol tetraoleate by "nonspecific lipase " (Mattson, F. H., and Volpenhein, R. A.,13 J. Lipid Res. 777 (1972)).
The same research group then fed a series of polyol fatty acid esters to rats (Mattson, F. H., and Nolen, G. A., 102 J. Nutr. 1171 (1972)). In a fat balance study, compounds having less than four hydroxyl groups esterified (specifically, methyl oleate, ethylene glycol oleate, and glycerol trioleate) were absorbed (Table 4, page 1174). As the number of ester groups increased (erythritol and pentaerythritol tetraoleate and xylitol pentaoleate), the absorbability decreased; sorbitol hexaoleate and sucrose octaoleate were not absorbed (ibid.). The investigators concluded that absorbability decreased by increasing the number of esterified hydroxyl groups (Discussion, page 1174, column 1 through page 1175, column 2).
The research was continued with a tracer study comparing the rates of absorption of fatty acids of fully esterified glycerol, erythritol, xylitol and sucrose as measured in thoracic duct cannulated rats (see Mattson, F. H., and Volpenhein, R. A., 102 J. Nutr. 1177 (1972)). Fatty acids fed as the erythritol tetraester appeared in the lymph at a slower rate than glycerol trioleate, but achieved the same level after 12 hours (see page 1179, column 1, lines 2-6 and column 2, FIGS. 2 and 3). Finding free tagged erythritol in the urine, the investigators concluded the tetraester was hydrolyzed in vivo (column 1, line 2 from to the bottom to column 2, line 8).
As a result of these studies, the investigators concluded that the number of hydroxyl groups esterified to be important indicia of digestibility, and patented the use of polyols, notably sucrose, having at least 4 hydroxyl groups esterified per molecule as low calorie fat replacements (see U.S. Pat. No. 3,600,186 to Mattson and Volpenhein and others following, such as, for example, U.S. Pat. No. 4,797,300 to Jandacek).
Nondigestible or nonabsorbable triglyceride analogues, polymeric materials, and polyol esters have proved disappointing as fat replacements when tested in feeding trials, where gastrointestinal side effects occurred, in some cases so extreme that frank anal leakage was observed (for recent reviews, see Hamm, D. J., 49 J. Food Sci. 419 (1984), Haumann, B. J., 63 J. Amer. Oil Chem. Soc. 278 (1986), and LaBarge, R. G., 42 Food Tech. 84 (1988)). Nondigestible fats act as a laxative and are expelled from the body, eliciting foreign body reactions like those early documented for mineral oil (Stryker, W. A., 31 Arch. Path. 670 (1941), more recently summarized in Goodman and Gilman's Pharmacological Basis of Therapeutics, 7th ed., Macmillan Pub. Co., N.Y. 1985, pp. 1002-1003). Polyglycerol and polyglycerol esters, for example, suggested as fat replacements supra, have been suggested for use as fecal softening agents as well (U.S. Pat. No. 3,495,010 to Fossel). A number of remedies have been recommended to combat the anal leakage observed when sucrose polyesters are ingested (e.g., employing cocoa butters, U.S. Pat. No. 4,005,195 to Jandacek, or incorporating saturated fatty groups, Eur. Pat. Ap. No. 233,856 to Bernhardt), and dietary fiber preparations have been incorporated into polysaccharide and/or polyol-containing foodstuffs to help inhibit the diarrheal effect (U.S. Pat. No. 4,304,768 to Staub et al.).
Subsequently, carboxy/carboxylates were suggested as edible, preferably partially digestible, fat mimetics (U.S. Pat. No. 4,830,787 to Klemann and Finley). These compounds have at least three aliphatic groups attached to a two- to five-carbon backbone with at least one conventional ester bond (forming a carboxy and/or methyl carboxy functionality) and at least one reversed ester bond (forming a carboxylate or methyl carboxylate functionality) as compared to conventional triglycerides. Preferred compounds were partially digestible, simultaneously achieving reduced caloric value while reducing problems associated with non-metabolizable fat substitutes. Polyoxyalkylene fatty acid esters have also been recently suggested as non-laxative fat replacements (U.S. Pat. No. 4,849,242 to Kershner).